The present invention relates to compositions containing lipase inhibitors, e.g. orlistat, and the use of said compositions for treating, reducing or preventing functional dyspepsia after ingestion of meals, especially of fat containing or fat rich meals.
Functional dyspepsia is a condition characterized by sensations of gastric fullness, nausea, bloating, gastric distress, etc., after intake of meals (even small meals), especially after intake of fat containing or fat rich meals. A large number of people are afflicted by this condition, continuously or more regularly in response to fat rich meals or fat rich meal items.
The arrival of lipid in the small intestinal lumen normally causes gastric relaxation, modulation of phasic motor activity, and pancreaticobiliary secretion. However, in patients with functional dyspepsia, lipids often provoke postprandial symptoms. Gastric and pancreatic lipases in the intestinal lumen hydrolyze triglycerides to free fatty acids, which may act on brain centers involved in dyspeptic symptoms.
Surprisingly, it has been found in a clinical model for functional dyspepsia that a lipase inhibitor, preferably orlistat, when administered orally, is useful in the treatment, reduction and prevention of functional dyspepsia. According to the present invention, inhibition of fat digestion reduces the intensity of postprandial dyspeptic symptoms.
The present invention relates to compositions containing lipase inhibitors, e.g. orlistat, and the use of said compositions for treating, reducing or preventing functional dyspepsia after ingestion of meals, especially of fat containing or fat rich meals.
Orlistat, a gastrointestinal lipase inhibitor, also known as XENCIAL(copyright), is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat, and U.S. Pat. No. 6,004,996, which discloses pharmaceutical compositions containing orlistat. Additional pharmaceutical compositions containing lipase inhibitors are described, for example, in International Patent Applications WO 00/09122, WO 00/09123, WO01/19340 and WO01/19378.
Additional processes for the preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359, 189,577, 443,449, and 524,495.
The addition of a lipase inhibitor such as orlistat (THL, tetrahydrolipstatin) to a fat emulsion infused into the duodenum reduced the intensity of stomach fullness and sensitivity, nausea and bloating in a clinical model of dyspepsia, that is, gastric distension represented by an inflatable balloon. This finding is very important as a large number of patients with digestive symptoms of unknown cause report that their symptoms frequently occur after ingestion of foods containing fat. Thus, by blocking the first step of intestinal lipid digestion these gastrointestinal symptoms can be aleviated using the compositions and methods of the present invention . Hence, the present invention has important clinical implications for the treatment of a subgroup of patients suffering from dyspepsia related to fat intolerance, in that partial inhibition of fat digestion may be an effective measure to relieve their symptoms. In summary, our data demonstrate the importance of inhibition of fat digestion for the suppression of postprandial symptoms.
The term xe2x80x9clipase inhibitorxe2x80x9d refers to compounds which are capable of inhibiting the action of lipases such as gastric and pancreatic lipases. Orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are examples of potent lipase inhibitors. Lipstatin is a natural product of microbial origin. Orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compounds commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, J. Antibiot., 47(12):1369-1375 (1994)). The term xe2x80x9clipase inhibitorxe2x80x9d includes synthetic lipase inhibitors such as those described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases. The term xe2x80x9clipase inhibitorxe2x80x9d also includes pharmaceutically acceptable salts of the foregoing compounds. In addition, the term xe2x80x9clipase inhibitorxe2x80x9d includes 2-oxy-4H-3,1-benzoxazin-4-ones which have been described in International Patent Application WO00/40569 (Alizyme Therapeutics Ltd.), e.g. 2-decyloxy-6-methyl-4H-3,1-benzooxazin-4-one, 6-methyl-2-tetradecyloxy-4H-3,1-benzoxazin-4-one, and 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one.
In a preferred embodiment, the present invention relates to the use of a lipase inhibitor fortreating, reducing or preventing functional dyspepsia. In particular the invention relates to the use of a lipase inhibitor to reduce the intensity of gastric fullness, nausea, and bloating during and after meal ingestion.
In an especially preferred embodiment of the present invention, the lipase inhibitor is orlistat.
The invention also relates to a method for treating, reducing or preventing functional dyspepsia comprising administering an effective amount of a gastrointestinal lipase inhibitor to a mammal, in particular a human, to reduce the intensity of fullness, nausea, bloating, or gastric distress following ingestion of fat rich meals or fat rich food items.
The preferred lipase inhibitor useful in the disclosed methods and compositions is orlistat. Preferably, the lipase inhibitor is administered orally.
The present invention also contemplates an oral composition for treating or preventing functional dyspepsia comprising an effective amount of a lipase inhibitor, preferably orlistat, and a pharmaceutically acceptable carrier or excipient.
The lipase inhibitor, e.g. orlistat, is administered at a dose of from about 30 to about 720 mg per day, preferably orally, in divided doses two to three times per day, most preferably during ingestion of fat rich foods.
Preferably, the dose of lipase inhibitors ranges from about 60 to about 360 mg, most preferably 360 mg per day
Most preferably the lipase inhibitor is administered orally, in divided doses, two, most preferably three, times per day. The subject may be a normal weight, an obese or overweight human.
The lipase inhibiting compositions of the invention are most useful when administered with a meal containing fat. Moreover, an additional benefit of the current invention is that other illnesses such as obesity and associated risk factors such as hypercholesterolemia, diabetes mellitus, etc. (described e.g. in U.S. Pat. No. 4,598,089 and International Patent Application WO98/34630) can be treated in parallel with the treatment of functional dyspepsia.
Orlistat can be administered to humans in conventional oral compositions, such as, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers which can be used for tablets, coated tablets, dragxc3xa9es and hard gelatin capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances. Alternatively, the lipase inhibitors may be administered in form of hard gelatine capsule or chewing tablets. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art (see above). Preferably, the lipase inhibitor, e.g. orlistat, may be administered according to the formulation shown in the Examples.